Alzheimer's disease (AD) is characterised by the presence of distinctive lesions in the victim's brain. These brain lesions include abnormal intracellular filaments called neurofibrillary tangles, and extracellular deposits of amyloid in senile, or amyloid, plaques. Amyloid deposits are also present in the walls of cerebral blood vessels of Alzheimer's patients.
The major constituent of amyloid plaques has been identified as a 4 kilodalton peptide (39-43 residues) called β-amyloid peptide (Aβ) (Glenner and Wong, 1984). Diffuse deposits of Aβ peptides are frequently observed in normal adult brains, whereas Alzheimer's disease brain tissue is characterised by more compacted, dense-core β-amyloid plaques. These observations suggest that Aβ deposition precedes, and contributes to, the destruction of neurons that occurs in Alzheimer's disease. In further support of a direct pathogenic role for AD, β-amyloid has been shown to be toxic to mature neurons both in culture and in vivo (Yanker et al., 1989).
Natural Aβ is derived from proteolysis from a much longer protein known as the amyloid precursor protein (APP) (Kang, J et al, 1987). The APP gene maps to chromosome 21, thereby providing an explanation for the β-amyloid deposition seen at an early age in individuals with Down's syndrome, which is caused by trisomy of chromosome 21.
Aβ peptides are cleaved from APP, and then undergo aggregation to produce the insoluble toxic β-sheet structures which are found in extracellular deposits in Alzheimer's disease and Down's syndrome. Recent data suggest that the aggregated peptide has redox properties and can generate reactive oxygen species, which attack enzymes and possibly cell membranes, causing neurotoxicity (Markesbery, W. R. 1997). Antitioxidants are known to protect against Aβ-induced toxicity.
Aβ has been shown to bind copper and iron in stoichiometric amounts, with the associated formation of reactive oxygen species such as peroxides and hydroxide radicals, which are possible sources of the neurotoxicity (Bush et al., 1998). While the formation of peroxide in post-mortem samples of Alzheimer's disease brain has been observed, there was little peroxide formation in control tissue (Cherny et al., 1998). The peroxidase activity observed in the samples of Alzheimer's disease brain was abolished when treated with certain chelators (Cherny et al., 1998). The formation of reactive oxygen species was accompanied by a reduction in the valence state of the metal, ie Cu(II) to Cu(I) and Fe(III) to Fe(II) (Atwood et al., 1998a). Reactive oxygen species can also lead to free radical formation on the Aβ peptide, which leads over time to covalent cross-linking of the Aβ peptides (Bush et al., 1998). In addition, a number of metal ions, including Zn, Ni and Cu, have been shown to induce aggregation of Aβ (Atwood et al., 1998b). When brain tissue from both control and Alzheimer's disease-affected subjects was treated with chelators which are specific for zinc and copper, there was greatly enhanced solubilisation of Aβ, with an increase of up to 700%, suggesting that zinc and copper play a role in the assembly of the Aβ deposits (Cherny et al., 1998).
Histidine residues have been implicated in the binding of metal ions to Aβ peptides. For instance rat Aβ1-40, in which His13 is mutated to Arg, does not aggregate, nor does Aβ1-40 treated with diethyl pyrocarbonate, which binds to the imidazole nitrogen of histidine (Atwood et al., 1998). Subsequently to the priority date of this application, it was reported that three histidine residues in the N-terminal hydrophilic region of human Aβ provide primary metal binding sites, and that the solubility of the complex between metal and Aβ depends on the mode of metal binding. The authors proposed that Cu2+ would protect Aβ against Zn-induced aggregation by competing with zinc ions for binding sites on the histidine residues (Miura et al., 2000).
In contrast, we propose that inhibition of binding of zinc, copper and/or iron to the Aβ peptide will have significant therapeutic value in the treatment of Alzheimer's disease.
It has been reported that certain tetrapyrroles, especially certain porphyrin and phthalocyanine compounds inhibit conversion of normal, protease-sensitive prion protein (PrPsen) to the protease-resistant form (PrPres) which is implicated in the pathogenesis of transmissible spongiform encephalopathies (TSEs) such as Creutzfeldt-Jacob disease (Caughey et al., 1998), and that three of these compounds inhibited TSE disease in vivo (Priola et al., 2000). However, both metal-free and metal-complexed tetrapyrroles were active, and the authors considered that the mechanism of action involved direct interaction between the compound and the infectious agent. Although the authors speculated that the compounds might also be useful in the treatment of non-prion mediated amyloid-related conditions, such as Alzehimer's disease or Type II diabetes, this was no more than speculation (Priola et al., 2000). Moreover, all of the compounds disclosed have multiple substitutions or the tetrapyrrole ring, whereas the tetrapyrrole compounds of the present invention are preferably substituted only on one of the rings.
It will be clearly understood that, although a number of prior art publications are referred to herein, this reference does not constitute an admission that any of these documents forms part of the common general knowledge in the art, in Australia or in any other country.